A Therapeutic Non-self-reactive SARS-CoV-2 Antibody Protects from Lung Pathology in a COVID-19 Hamster Model

Cell. 2020 Nov 12;183(4):1058-1069.e19. doi: 10.1016/j.cell.2020.09.049. Epub 2020 Sep 23.

Abstract

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from 10 COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb, CV07-209, neutralized authentic SARS-CoV-2 with an IC50 value of 3.1 ng/mL. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 Å revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2-neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss, and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

Keywords: COVID-19; SARS-CoV-2; autoreactivity; crystal structures; hamster model; monoclonal antibody; neutralizing antibody; post-exposure; self-antigens; self-reactivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology*
  • Antibodies, Viral / therapeutic use
  • Antigen-Antibody Reactions
  • Betacoronavirus / immunology
  • Betacoronavirus / metabolism*
  • Betacoronavirus / pathogenicity
  • Binding Sites
  • COVID-19
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / pathology*
  • Coronavirus Infections / virology
  • Cricetinae
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Humans
  • Kinetics
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Molecular Dynamics Simulation
  • Pandemics
  • Peptidyl-Dipeptidase A / chemistry
  • Peptidyl-Dipeptidase A / metabolism
  • Pneumonia, Viral / drug therapy
  • Pneumonia, Viral / pathology*
  • Pneumonia, Viral / virology
  • Protein Binding
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / immunology
  • Spike Glycoprotein, Coronavirus / metabolism

Substances

  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2